Integrated genotype-phenotype function analysis reveals distinct pathogenic mechanisms for cognitive impairment in...

Pathogenic variants of KCNQ2 lead to a spectrum of disorders including self-limited familial neonatal-infantile epilepsy (SeL(F)NIE), developmental and epileptic encephalopathies (DEEs), and neurodevelopmental disorders (NDDs) with intellectual disability (ID). This study aimed to delineate the clinical progression and underlying pathogenesis of these disorders. Particularly, we unraveled the role of gain-of-function (GoF) variants in neurodevelopmental impairment.

We conducted a longitudinal study of a 90-patient Chinese cohort with KCNQ2-related disorders, classified into SeL(F)NIE, DEEs, and NDDs subgroups. Clinical phenotyping was integrated with functional analyses (electrophysiology, biochemistry) of five missense variants in homomeric and heteromeric (with Kv7.3/Kv7.5) channel assemblies.

Despite comparable seizure control to SeL(F)NIE (96% vs 100%), the NDDs group exhibited significant cognitive impairment. All deceased patients (8/90) were in the DEEs group. Functional profiling revealed a spectrum from loss-of-function (LoF) to GoF. LoF variants (e.g., S247L in DEEs) were linked to severe epilepsy. Crucially, we identified strong GoF variants (P335A/L in NDDs) in the S6-HelixA domain that confer insensitivity to phosphatidylinositol 4,5-bisphosphate (PIP₂) regulation and are associated with a primary neurodevelopmental phenotype, distinct from the severe epileptic phenotype of established voltage-sensing domain (VSD) GoF variants.

Our integrated clinical and functional analysis showed that the clinical outcome relies on the functional consequence of a KCNQ2 variant (LoF vs GoF) and its behavior in heteromeric complexes, rather than its mere location. We defined a novel class of strong GoF KCNQ2 variants that are mechanistically and phenotypically distinct, highlighting aberrantly enhanced channel function as a key driver of cognitive dysfunction and presenting new targets for precision medicine.